The consequences of alcohol abuse on the American public are profound, both in terms of individual well-being and impact on the family structure, as well as the enormous cost to society in terms of lost productivity and associated health care expenses. Despite increasing efforts, our understanding of the neurobiological mechanisms that underlie the effects of alcohol and the development of alcohol use disorders remains incomplete. Epidemiological research has pointed to adolescence as a critical period in the development of alcohol disorders. One area of the brain that appears especially vulnerable to the effects of alcohol is the prefrontal cortex (PFC), which remains immature at the onset of adolescence. The PFC is involved in decision- making, memory and impulse control, behaviors that are often disrupted following consumption of alcohol and are believed to underlie long-term addiction. In the PFC, pharmacologically relevant doses of alcohol are known to depress neuronal activity (Tu et al. 2007), but very little is known of its interactions with the inhibitor receptors, GABA and glycine, within the PFC. This is despite the expression of GABA-A receptor subtypes in the PFC (Hoestgaard-Jensen et al. 2010) that mediate tonic inhibition in other brain regions and demonstrate high sensitivity to alcohol (Wei et al. 2004, Jia et al. 2008). In addition, we note that functional glycine receptors are also present in PFC (Ye et al. 2011) but have received little to no attention. The goal of this research proposal is to examine the pharmacological actions of alcohol on neuronal excitability and on GABA and glycine-mediated synaptic and tonic inhibition in the adolescent PFC, and to determine if chronic alcohol drinking during adolescence leads to specific alterations of inhibition that affect neuronal excitability. Tis information could enhance our understanding of the negative effects of alcohol drinking during adolescence and an increased focus on cellular mechanisms involved can help lead to the development of therapeutic strategies to treat alcohol use disorders. PUBLIC HEALTH RELEVANCE: Drinking alcohol during adolescence is a major public health concern as it often leads to alcohol and substance abuse disorders later in life. The goal of this proposal is to better understand the effects of alcohol on the adolescent brain which will be accomplished by measuring changes in brain cell activity in animals that drink alcohol during adolescence. Findings from this work will raise awareness on alcohol vulnerability during adolescence and could lead to the development of medicines that treat alcohol use disorders.